Excessive ethanol consumption induces neurotoxicity that may involve neuroinflammation. Microglia are the primary immune cells in the central nervous system (CNS) and have been implicated as a major contributor to neuroinflammation-related neurotoxicity; however, the role of microglia in alcohol- induced neuronal dysfunction is not fully understood especially in the context of neuron-microglia interplay. In this proposal, we will employ novel proteomic methods to identify and quantify differential protein expression to test our working hypothesis that the interplay of microglia with surrounding neurons plays a pivotal role in alcohol-induced microglial activation and subsequent neurotoxicity. We propose to determine the ethanol-induced microglial response in an in vivo model of chronic ethanol exposure using a novel Super-SILAC approach. Changes identified by Super- SILAC proteomic profiling will be mapped to miRNA differential expression to establish a global-scale mechanistic network featuring non-coding RNAs and their regulatory role in protein expression. The results from our proposed studies will provide further insight into the role of microglia in ethanol- induced neurodegeneration and identify potential targets for new therapeutic strategies for the treatment or prevention of neuronal injury brought about by excessive and long-term alcohol consumption.